This proposal presents a five-year research career development program focused on the study of HIV-1 latency and eradication at the interface between virology and immunology. The candidate is currently an Instructor of Medicine at Harvard Medical School in the Division of Infectious Diseases at the Brigham and Women's Hospital. The outlined proposal builds on the candidate's previous research and clinical experience and integrates the two distinct domains of expertise represented by her mentor team of Dr. Daniel Kuritzkes and Dr. Marcus Altfeld. The proposed experiments and didactic work will position the candidate with a unique set of cross-disciplinary skills that will enable her transitin to independence as a physician scientist working in the field of HIV eradication. Despite remarkable advances in the medical management of HIV-1 infection, the epidemic continues to present clinical, social and economic challenges on a global scale. Strategies to interrupt and contain the epidemic are urgently needed. The recent description of isolated cases of functional cure of HIV-1 infection has turned attention to the possibility of virus eradication to achieve thi goal. The feasibility of this approach depends on both the development of targeted agents for HIV-1 latency reversal and on the successful elimination of cells harboring reactivating virus. This proposal focuses on the latter question, with the goal of developing a novel approach to enhance immune clearance of the HIV-1 reservoir. In place of the traditional focus on epitope or antigen specific adaptive immune responses, this proposal seeks to use the innate immune natural killer (NK) cell population to rapidly identify generic signals of stress and infection on reservoir cells through the NKG2D receptor. To enhance this system of detection, the studies proposed will also test the efficacy of blocking the HIV-1 protein Nef to abrogate its immune evasion functions. Specific aims of this proposal include 1) to define both the kinetics of expression NKG2D ligands on CD4 T cells after disruption of HIV-1 latency and the signals responsible for initial expression, 2) to enhance expression of NKG2D ligands through inhibition of HIV-1 Nef, and identify the required domain(s) of Nef and 3) to demonstrate that sustained NKG2D ligand expression after latency reversal and inhibition of Nef leads to enhanced NK cell effector function. Positive results from these studies would provide the foundation for early clinical trials of a combined strategy of latency reversal and Nef blockade.